Chronic Lymphocytic Research Articles

Is maintenance therapy following previous treatment better than observation or placebo for treating chronic lymphocytic leukaemia in adults? (Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review)

This publication is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review: Lee C-H, Wu Y-Y, Huang T-C, Lin C, Zou Y-F, Cheng J-C, Chen P-H, Jhou H-J, Ho C-L. Maintenance therapy for chronic lymphocytic leukaemia. Cochrane Database of Systematic Reviews 2024, Issue 1. Art. No.: CD013474. DOI: 10.1002/14651858.CD013474.pub2

Detection of disease-specific signatures in B cell repertoires of lymphomas using machine learning.

The classification of B cell lymphomas-mainly based on light microscopy evaluation by a pathologist-requires many years of training. Since the B cell receptor (BCR) of the lymphoma clonotype and the microenvironmental immune architecture are important features discriminating different lymphoma subsets, we asked whether BCR repertoire next-generation sequencing (NGS) of lymphoma-infiltrated tissues in conjunction with machine learning algorithms could have diagnostic utility in the subclassification of these cancers. We trained a random forest and a linear classifier via logistic regression based on patterns of clonal distribution, VDJ gene usage and physico-chemical properties of the top-n most frequently represented clonotypes in the BCR repertoires of 620 paradigmatic lymphoma samples-nodular lymphocyte predominant B cell lymphoma (NLPBL), diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL)-alongside with 291 control samples. With regard to DLBCL and CLL, the models demonstrated optimal performance when utilizing only the most prevalent clonotype for classification, while in NLPBL-that has a dominant background of non-malignant bystander cells-a broader array of clonotypes enhanced model accuracy. Surprisingly, the straightforward logistic regression model performed best in this seemingly complex classification problem, suggesting linear separability in our chosen dimensions. It achieved a weighted F1-score of 0.84 on a test cohort including 125 samples from all three lymphoma entities and 58 samples from healthy individuals. Together, we provide proof-of-concept that at least the 3 studied lymphoma entities can be differentiated from each other using BCR repertoire NGS on lymphoma-infiltrated tissues by a trained machine learning model.

Cold plasma treatment of patient‐derived chronic lymphocytic B‐cell leukemia enhances cytotoxic T‐cell proliferation

AbstractCold physical plasma, a partially ionized gas, has been shown to be effective in treating chronic wounds and cancer. However, there is limited research on plasma exposure of leukemia cell lines, such as chronic lymphocytic leukemia (CLL) and cytotoxic CD8+ T cells. To investigate the potential proimmunogenic effects of plasma‐derived reactive oxygen species, cytotoxic T cells were isolated from CLL patients and healthy volunteers. Extensive cold plasma treatment reduced T‐cell metabolic activity and viability in both diseased and healthy groups. Plasma treatment of cocultures, but not CD8+ T‐cell monocultures, spurred cytotoxic T‐cell proliferation, possibly due to plasma‐enhanced CLL antigen display and plasma‐mediated modulation of immunoregulatory surface molecules. Further studies are needed to understand the mechanisms and clinical relevance of these findings.

Tp53 Genetic Mutations in Chronic Lymphocytic Leukemia Patients in Iraq

Abstract BACKGROUND: Chronic lymphocytic leukemia (CLL) is a malignant clonal proliferative condition of mature CD5+ B cells, with a 4.2/100,000 annual incidence rate and the median age at diagnosis is 72 years. CLL impacts mainly the elderly in Western nations. About 4%–10% of patients have 17p deleted at diagnosis, which includes tumor-suppressor protein (TP53) gene deletions and/or mutations. However, TP53 can also be acquired during the course of the disease, with a predictable incidence of 42%–45% in refractory CLL. Even when this mutation develops in a small percentage of neoplastic cells, the attending of subclonal TP53 changes has been linked to a bad prognosis. TP53 mutations are correlated with significantly lower lifespan and indicate impaired tolerance to chemoimmunotherapy, making them among the most powerful prognostic markers-guiding treatment decisions in CLL. MATERIALS AND METHODS: This cross-sectional study was performed at different centers in Iraq, including Euphrates Center for Cancerous Tumors, Najaf, and the Hematology center-medical City, Baghdad, Imam al Hussien Medical City, Karbala, from October 2023 to June 2024, with patients diagnosed by blood film and immunophenotyping CLL, included 63 patients. RESULTS: DNA Sequencing of TP53 genes investigated by Sanger technique to detect TP53 variations. All potential genotype variations of the TP53 gene were detected across several single-nucleotide polymorphisms (SNPs). CONCLUSIONS: The vast majority, 93% of our patients, carry variant-type mutations of TP53. The genotype of SNP rs1597359353 was found P < 0.05, which is significant according to the White blood count (WBCs) count, although all patients on treatment or follow-up had TP53 mutations.

Realizing precision medicine in chronic lymphocytic leukemia: Remaining challenges and potential opportunities.

Patients with chronic lymphocytic leukemia (CLL) exhibit diverse clinical outcomes. An expanding array of genetic tests is now employed to facilitate the identification of patients with high-risk disease and inform treatment decisions. These tests encompass molecular cytogenetic analysis, focusing on recurrent chromosomal alterations, particularly del(17p). Additionally, sequencing is utilized to identify TP53 mutations and to determine the somatic hypermutation status of the immunoglobulin heavy variable gene. Concurrently, a swift advancement of targeted treatment has led to the implementation of novel strategies for patients with CLL, including kinase and BCL2 inhibitors. This review explores both current and emerging diagnostic tests aimed at identifying high-risk patients who should benefit from targeted therapies. We outline existing treatment paradigms, emphasizing the importance of matching the right treatment to the right patient beyond genetic stratification, considering the crucial balance between safety and efficacy. We also take into consideration the practical and logistical issues when choosing a management strategy for each individual patient. Furthermore, we delve into the mechanisms underlying therapy resistance and stress the relevance of monitoring measurable residual disease to guide treatment decisions. Finally, we underscore the necessity of aggregating real-world data, adopting a global perspective, and ensuring patient engagement. Taken together, we argue that precision medicine is not the mere application of precision diagnostics and accessibility of precision therapies in CLL but encompasses various aspects of the patient journey (e.g., lifestyle exposures and comorbidities) and their preferences toward achieving true personalized medicine for patients with CLL.

Australians with chronic lymphocytic leukaemia continue to have high rates of second primary malignancies in the modern era.

Population-based studies have demonstrated a high risk of second cancers, especially of the skin, among patients with chronic lymphocytic leukaemia (CLL). We describe age-standardised incidence ratios (SIRs) of second primary malignancies (SPM) in Australian patients with relapsed/refractory CLL treated with at least two lines of therapy, including ibrutinib. From December 2014 to November 2017, 156 patients were identified from 13 sites enrolled in the Australasian Lymphoma and Related Diseases Registry, and 111 had follow-up data on rates of SPM. At 38.4 months from ibrutinib therapy commencement, 25% experienced any SPM. SIR for melanoma and all cancers (excluding nonmelanomatous skin cancers) were 15.8 (95% confidence interval (CI): 7.0-35.3) and 4.6 (95% CI: 3.1-6.9) respectively. These data highlight the importance of primary preventive interventions and surveillance, particularly as survival from CLL continues to improve.

Safety and efficacy of acalabrutinib and obinutuzumab in treatment-naive chronic lymphocytic leukemia: a Japanese phase 1 study

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

Correction to “Activated Galectin‐9/Tim3 promotes Treg and suppresses Th1 effector function in chronic lymphocytic leukemia”

Correction to “Activated Galectin‐9/Tim3 promotes Treg and suppresses Th1 effector function in chronic lymphocytic leukemia”

The Impact of Anemia on the Survival of Patients Diagnosed With Low-Grade Malignant B-cell Lymphomas.

B-cell lymphomas with a low degree of malignancy represent a heterogeneous group of diseases, that evolve slowly, butpresent particularities in terms of long-term survival. We investigated the impact of anemia from the time of diagnosis in 249 patients with malignant B-cell lymphomas, diagnosed between January 2011 and December 2015, in the Hematology Department of the Sibiu County Emergency Hospital, Romania. We included 126(50.6%) male and 123 (49.4%) female patients with the average age being 68.2 years. Among all patients, 106 (42.6%) were diagnosed with chronic lymphocytic leukemia (CLL), 61 (24.5%) with marginal zone lymphoma (MZL), 53 (21.3%) with multiple myeloma (MM), 16 (6.4%) with follicular lymphoma (FL), nine (3.6%) with plasmacytoma, and four cases with hairy cell leukemia (HCL). The serum Hb value in the subject group varied between 2.6 g/dL and 17 g/dL.At diagnosis, 18 (7.2%) patients had severe anemia, 32 (12.9%)had moderate anemia, 58 (23.3%) had mild anemia, and 141 (56.6%) had no anemia at all at the time of diagnosis. In our group, the higher degree of anemia was correlated with a more advanced stage of the disease but not with the older age of the patients. Our study's highest median value of LDH corresponded to moderate anemiaand the lowest value to patients who did not have anemia. Patients who did not have anemia at diagnosis had the best survival at five years, followed by those with mild anemia, then those with moderate anemia. In our cohort, subjects with the lowest Hb value at diagnosis had the worst survival. The results of our study conclude that anemia represents a negative impact factor not only on the patient's quality of life but also on their survival.

Cardiac arrhythmias and overall outcomes with Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia

Cardiac arrhythmias and overall outcomes with Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia

CD49d expression is included in a revised 4-factor model predicting outcome in patients with chronic lymphocytic leukemia treated with ibrutinib: A multicenter real-world experience.

CD49d expression is included in a revised 4-factor model predicting outcome in patients with chronic lymphocytic leukemia treated with ibrutinib: A multicenter real-world experience.

Two Novel Precursors of HIV-1 Proteases Inhibitors as a Novel Anticancer Treatment on Multiple Myeloma and Chronic Lymphocytic Leukemia Cell Lines

Two Novel Precursors of HIV-1 Proteases Inhibitors as a Novel Anticancer Treatment on Multiple Myeloma and Chronic Lymphocytic Leukemia Cell Lines

Central nervous system involvement of chronic lymphocytic leukaemia: A rare case report

Central nervous system (CNS) involvement in chronic lymphocytic leukemia (CLL) is unfamiliar. The diagnosis is delayed commonly, because of underdiagnosis or subclinical symptoms. We describe a 80-year-old woman with a previous diagnosis of CLL who presented to the emergency service with tonic clonic seizure. The new therapies, eg, ibrutinib and venetoclax, can be effective treatment strategies for CLL with CNS involvement. In our case, treatment with ibrutinib led to a resolution of the cerebralspinal fluid (CSF) neoplastic infiltration, but the patient died afterwards.

Expert opinion on use of acalabrutinib for chronic lymphocytic leukemia treatment

Expert opinion on use of acalabrutinib for chronic lymphocytic leukemia treatment

Evaluation of PD-1 / PD-L1 Expressions in Patients with Diffuse Large B Cell Lymphoma and Chronic Lymphocytic Leukemia

ÖZET Amaç: Programlanmış ölüm 1 (PD-1) / PD-ligandı (PDL) yolu, T hücresi aracılı immün yanıtlarının düzenlenmesi için önemli bir kontrol noktasıdır. Kanserler ne yazık ki PD-1/ PD-L1 yolunun immünsüpresif etkilerinden de yararlanmaktadır. Yaygın Büyük B Hücreli Lenfoma ( YBBHL) ve Kronik Lenfositer Lösemi (KLL)'de PD-1/ PD-L1’in önemi ile ilgili yeterli kanıt yoktur. Çalışmamızda YBBHL ve KLL’de PD-1/ PD-L1 ekspresyonun varlığını ve prognostik önemini değerlendirmeyi amaçladık. Gereçler ve Yöntem: Hematoloji Kliniğinde Ocak 2010 ile Eylül 2018 tarihleri arasında takip edilen 18-80 yaş arası 26 YBBHL hastası ve 27 KLL hastası çalışmaya dahil edildi. İmmunhistokimyasal boyama için Tıbbi Patoloji Anabilim Dalı arşivinde bulunan hastalara ait parafin blokları kullanıldı. YBBHL hastalarının lenf bezi biyopsi materyalleri ve KLL hastalarının kemik iliği biyopsi materyalleri değerlendirildi. PD-1 neoplastik olmayan dokularda boyandı ve PD-L1 neoplastik hücrelerde boyandı. Boyanma yüzdesi %5'in üzerinde olanlar pozitif kabul edildi. Bulgular: PD-1; YBBHL olgularının %65,4’ünde (n=17) pozitif, KLL olgularının %14,8’inde (n=4) pozitif saptandı. PD-L1; YBBHL olgularının %69,2’sinde (n=18) pozitif, KLL olgularının PD-L1 %3,7’sinde (n=1) pozitif saptandı. PD-1 ve PD-L1 ekspresyon ve boyanma sıklığı istatistiksel olarak anlamlı şekilde YBBHL’da daha yüksek bulundu (p=<0.001). PD-L1’de YBBHL tanılı olgularda evreler arasında ekspresyon açısında anlamlı fark bulundu (P=0,004). Sonuç: Çalışmamızda YBBHL’de literatürden daha yüksek oranda PD-1/ PD-L1 ekspresyonu tespit edildi. KLL’de diğer çalışmalara göre daha düşük oranda PD-1/PD-L1ekspresyonu saptandı. PD-1/ PD-L1 ekspresyonun YBBHL’de KLL’den daha fazla olduğu gösterildi. Anahtar Kelimeler: Yaygın Büyük B Hücreli Lenfoma, Kronik Lenfositer Lösemi, PD-1, PD-L1.

Decoding the Interplay: Exploring Immunotherapy Resistance in the Tumor Microenvironment

The tumor microenvironment (TME) surrounds the tumor and includes blood vessels, immune cells, fibroblasts, signaling molecules, and the extracellular matrix. This review examines the cellular components and pathways within the TME, highlighting their potential as targets for immunotherapy. It also covers recent advances from the past several years in TME, immunotherapy, and combination therapy. The review emphasizes the role of CD8+ T cells in the TME and their relevance to immunotherapy. It discusses various T cell-targeted treatments, including PD-1/PDL1, CTLA-4, VEGF, Interferon-ɣ, LAG-3, and ER stress-XBP1. Recognizing the complexity and uniqueness of each tumor's immunotherapy network, the review aims to understand and compare the TMEs of different cancers and the respective immunotherapies. Cancers covered include non-small cell lung Cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), cervical cancer, chronic lymphocytic leukemia, and gastric cancers. The review also addresses future research directions and applications of immunotherapies, aspiring to advance TME understanding and research.

P010 Eosinophilic dermatosis of haematological malignancy mimicking insect bite-like reaction in a patient with chronic lymphocytic leukaemia: a case report

P010 Eosinophilic dermatosis of haematological malignancy mimicking insect bite-like reaction in a patient with chronic lymphocytic leukaemia: a case report

Odds of developing cancer among male and female volunteer firefighters in Florida: A case-control study design.

Determine whether volunteer firefighters in Florida are at increased odds of developing cancer compared to non-firefighters. A case-control study design was implemented to assess the odds of developing cancer among male and female volunteer firefighters in Florida. Gender-specific age and calendar year-adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) were estimated. Male volunteer firefighters were at increased odds for developing prostate (aOR = 1.26; 95%CI;[1.10- 1.44]) and male genital cancers combined (1.22;[1.07-1.39]), while reduced odds for endocrine cancer (0.41;[0.17-1.00]), and all leukemias (0.55;[0.35-0.86]), including lymphocytic (0.48;[0.24-0.97]); and chronic lymphocytic (0.40;[0.17-0.97]) leukemias. Female volunteer firefighters were at increased odds of developing of kidney cancer (2.51;[1.29-4.91]). Male volunteer firefighters are at increased odds for prostate and overall male genital cancers, while female volunteers are increased odds of kidney cancer.

Overall survival of patients with CLL treated with ibrutinib in the first line compared to second-line ibrutinib after chemotherapy/chemoimmunotherapy

Objective To evaluate the overall survival (OS) of patients with chronic lymphocytic leukemia (CLL) receiving either ibrutinib monotherapy as a first-line (1L) treatment or chemotherapy/chemoimmunotherapy-based (CT/CIT) regimens in 1L followed by ibrutinib in the second line (1L CT/CIT-2L ibrutinib) after disease progression by emulating a randomized trial comparing both treatment sequences. Methods Patient-level data from the RESONATE-2 trial (NCT01722487) and real-world PHEDRA databases were analyzed. Three scenarios were considered using the following data sources: (1) RESONATE-2, (2) combined RESONATE-2/PHEDRA, (3) combined RESONATE-2/PHEDRA for 1L ibrutinib and PHEDRA for 1L CT/CIT-2L ibrutinib. Propensity score-based weights and inverse probability of censoring weighting were used to adjust for baseline (Scenarios 2 and 3) and time-dependent confounding (all scenarios), and to address potential biases. A weighted Cox proportional hazards model was used to estimate the OS hazard ratio (HR) and 95% confidence interval (CI) for 1L ibrutinib versus 1L CT/CIT-2L ibrutinib. Results Results from Scenario 1 showed a significantly lower risk of death with 1L ibrutinib compared with 1L chlorambucil followed by 2L ibrutinib (HR 0.35 [95% CI 0.20–0.62]). Results from Scenarios 2 and 3 demonstrated a reduced risk of death with 1L ibrutinib compared with 1L CT/CIT-2L ibrutinib (HR 0.35 [0.21–0.61] and 0.64 [0.39–1.04], respectively). Conclusion The analyses consistently showed a reduced risk of death when ibrutinib was used as a 1L treatment in CLL compared with delaying its use until 2L after CT/CIT regimens, which suggests that initiating ibrutinib in 1L is advantageous for improving survival outcomes.

In-vivo pharmacokinetic study of ibrutinib-loaded nanostructured lipid carriers in rat plasma by sensitive spectrofluorimetric method using harmonized approach of quality by design and white analytical chemistry

Ibrutinib, an antineoplastic agent tackling chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s Macroglobulinemia, falls under the category of BCS class II drugs, characterized by a puzzling combination of low solubility and high permeability. Its oral bioavailability remains a perplexing challenge, merely reaching 2.9 % due to formidable first-pass metabolism hurdles. In a bid to surmount this obstacle, researchers embarked on a journey to develop ibrutinib-loaded NLCs (Nanostructured Lipid Carriers) using a methodology steeped in complexity: a Design of Experiments (DoE)-based hot melted ultrasonication approach. Despite a plethora of methods for analyzing ibrutinib in various matrices, the absence of a spectrofluorimetric method for assessing it in rat plasma added to the enigma. Thus emerged a spectrofluorimetric method, embodying principles of white analytical chemistry and analytical quality by design, employing a Placket-Burman design for initial method exploration and a central composite design for subsequent refinement. This method underwent rigorous validation in accordance with ICH guidelines, paving the way for its application in scrutinizing the in-vivo pharmacokinetics of ibrutinib-loaded NLCs, juxtaposed against commercially available formulations. Surprisingly, the optimized NLCs exhibited a striking 1.82-fold boost in oral bioavailability, shedding light on their potential efficacy. The environmental impact of this method was scrutinized using analytical greenness tools, affirming its eco-friendly attributes. In essence, the culmination of these efforts has not only propelled advancements in drug bioavailability but also heralded the dawn of a streamlined and environmentally conscious analytical paradigm.